Melanoma is the most lethal skin tumour, and its incidence is rising. Metastatic melanoma is refractory to treatment and is associated with a very poor prognosis. Advanced/metastatic melanoma frequently harbours mutations in the RAS-BRAF-MAPK oncogene and in the p16ink4A-Rb and p14Arf-p53 tumour suppressor pathways. Around 20% and 44% of melanomas harbor active mutations of N-RAS and B-RAF, respectively, and these tumours have elevated RAS/RAF kinase activities (Forbes et al., 2006). Similarly, deletion in the p16ink4A locus, which will inactivate both p16ink4a and p14Arf, also occurs in around 50% of melanomas (Curtin et al., 2005). P16ink4a is an inhibitor of cyclin dependent kinases, cyclinD1/cdk4 in particular. Melanomas containing p16ink4a mutations will have elevated cyclinD1/cdk4 kinase activity that will in turn phosphorylate the tumour suppressor Rb and inactivate its ability to arrest the cell at G1 phase of the cell cycle. Mutation of p14Arf will remove its ability to block the action of mdm2, an inhibitor and E3 ubiquitin ligase of p53. As a result, p14Arf mutant melanoma cells may have wild type p53, but its tumour suppressive functions are lost. The importance of RAS-RAF oncogene and p16ink4a/Rb and p14Arf/p53 tumour suppressor pathways in the development and maintenance of melanomas is underscored by a plethora of experimental evidence. This knowledge has led to the recent success of B-RAF inhibitors, such as PLX4032, as new melanoma therapeutic agents. PLX4032 selectively inhibits proliferation of tumour cells that harbour the B-RafV600E mutation (Joseph et al., 2010). Despite promising efficacy in inhibiting melanoma growth in the initial stages of treatment, the majority of PLX4032 treated patients relapsed within a few months, largely due to acquired drug resistance. As expected, the majority of the drug resistance was caused by mutations affecting the RAS/MAPK pathways (Chapman et al., 2011; Cox and Der, 2012; Johannessen et al., 2010; Nazarian et al., 2010; Poulikakos and Rosen, 2011; Poulikakos and Solit, 2011). (Chapman et al., 2011; Johannessen et al., 2010; Nazarian et al., 2010). To overcome acquired drug resistance, co-targeting B-RAFV600E and MEK has been suggested (Poulikakos 2011). As both B-RAF and MEK are in the same pathway, it is difficult to predict whether targeting these two components of the same pathway will be sufficient to eliminate all melanoma cells. An alternative strategy would be to induce synthetic lethality of melanoma cells by co-targeting two independent pathways that are both critical in melanoma development and maintenance.
The tumor suppressor p53 pathway is of particular interest. B-RAFV600E is present in around 50% of human melanomas; however, 80% of human melanomas express wild type p53 implying that a large number of B-RAFV600E melanomas also contain wild type p53. It has been established that growth suppression induced by B-RAFV600E inhibitors is independent of p53. It is also known that the tumor suppressive function of p53 is largely lost in melanoma cells expressing wild type p53 expressing tumors.
Overexpression of mdm2 or and mdmX are two inhibitors of p53, has been observed in melanomas, and this was shown to contribute to the inactivation of wild type p53 function (Muthusamy et al., 2006; Polsky et al., 2001). To restore the tumor suppressive function of p53 in human tumors, including melanomas that express wild type p53, agonists of p53 such as Nutlin3 have been developed and tested in Phase II clinical trials. Nutlin3 suppresses tumor growth by inducing cell cycle arrest through it ability to prevent mdm2 from targeting p53 for degradation. Unfortunately, nutlin3 failed to reactivate p53 in all wild type p53-expressing melanoma cells (de Lange et al., 2011; Ji et al., 2011). It is therefore important to identify an alternative strategy for reactivating the tumor suppressing function of p53 in melanoma cells.
A need exists for modulators of apoptosis. For example, pro-apoptotic modulators may be useful for treating or palliating cancers or other conditions characterized by undesirable or uncontrolled cell growth. Anti-apoptotic factors may be useful for treating or palliating degenerative conditions.